European Heart Journal (2023) 44, 643–655 STATE OF THE ART REVIEW

https://doi.org/10.1093/eurheartj/ehac759 Heart failure and cardiomyopathies

Endocrine functions of the heart: from bench

to bedside
1,2 1
Massimo Volpe *, Giovanna Gallo , and Speranza Rubattu1,3
1
Department of Clinical and Molecular Medicine, Sapienza University of Rome, Via di Grottarossa 1035, 00189 Rome, Italy; 2IRCCS San Raffaele, Via della Pisana 235, 00163 Rome, Italy; and

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3
IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli (IS), Italy

Received 11 July 2022; revised 22 November 2022; accepted 5 December 2022; online publish-ahead-of-print 30 December 2022

Graphical Abstract

FFA oxidation
GH secretion
Regulation of body growth

Natriuresis/diuresis
GLP-1
RAAS inhibition
Insulin secretion
Blood volume reduction

Endocrine
Endo
Endocrine ffunction
unction off tthe
he heart
he
earr t
Natriu
Na
Natriuretic
ri retic
etic peptides
tide
Other cardiac hormones
Vasorelaxation Oxygen consumption
BP reduction FFA oxidation
Increased capillary Regulation of muscle mass
permeability

Lipolysis
SNS inhibition
Postprandial energy expenditure
Reduced AVP secrection
Mitochondrial respiration

The graphical abstract illustrates the systemic effects of NPs and other hormones secreted from the heart, their peripheral effects, and the inter­
actions with other endocrine systems. AVP, arginine vasopressin; BP, blood pressure; FFA, free fatty acid; GH, growth hormone; GLP-1, glucagon like
peptide-1; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.

* Corresponding author. Tel: +39 06 33775979, Fax: +39 06 33775546, Email: massimo.volpe@uniroma1.it
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
644 M. Volpe et al.

Abstract

Heart has a recognized endocrine function as it produces several biologically active substances with hormonal properties. Among these hormones,
the natriuretic peptide (NP) system has been extensively characterized and represents a prominent expression of the endocrine function of the
heart. Over the years, knowledge about the mechanisms governing their synthesis, secretion, processing, and receptors interaction of NPs has
been intensively investigated. Their main physiological endocrine and paracrine effects on cardiovascular and renal systems are mostly mediated
through guanylate cyclase-A coupled receptors. The potential role of NPs in the pathophysiology of heart failure and particularly their counterbal­
ancing action opposing the overactivation of renin-angiotensin-aldosterone and sympathetic nervous systems has been described. In addition, NPs
are used today as key biomarkers in cardiovascular diseases with both diagnostic and prognostic significance. On these premises, multiple therapeutic
strategies based on the biological properties of NPs have been attempted to develop new cardiovascular therapies. Apart from the introduction of
the class of angiotensin receptor/neprilysin inhibitors in the current management of heart failure, novel promising molecules, including M-atrial natri­

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uretic peptide (a novel atrial NP-based compound), have been tested for the treatment of human hypertension. The development of new drugs is
currently underway, and we are probably only at the dawn of novel NPs-based therapeutic strategies. The present article also provides an updated
overview of the regulation of NPs synthesis and secretion by microRNAs and epigenetics as well as interactions of cardiac hormones with other
endocrine systems.
.............................................................................................................................................................................................
Keywords Cardiac natriuretic peptides • Secretion • Epigenetics • Cardiovascular diseases • Biomarkers • Therapy

with relevant consequences on BP, blood volume, and electrolyte

Historical landmarks of the
endocrine heart
Following the development of the concept of endocrine glands in the se­
cond half of the XIX century, through the pioneering discoveries of
Claude Bernard on the glucose secretion by the liver into the portal
vein ‘milieu interieur’1 and of the studies of Thomas Addison in adrena­
lectomized animals,1 in 1898 Camillo Golgi described cytoplasmic bod­
ies containing hormones.2 In the early ’50s, Jameson and Palade
established the function of the Golgi apparatus in secretory protein traf­
ficking,3 while Kisch4 in 1956 demonstrated the presence of the secre­
tory granules in mammalian atria. At the same time, Gauer and Henry
demonstrated that the cardiac atria could sense the ‘fullness’ of the car­
diovascular system and produce adjustments in renal salt and water ex­
cretion to maintain a constant blood volume.5 In their experiments,
stretching the atrium by balloon inflation of anaesthetized dogs resulted
in enhanced diuresis and natriuresis in animals kept on parallel
circulation.5
Based on this integrated evidence, the ‘smoking gun’ of the heart
functioning as an endocrine gland was under the eyes. The discovery
of cardiac hormones had to wait three more decades, until in 1981
Adolfo De Bold and colleagues reported that atrial extracts contained
an active peptide, initially named as atrial natriuretic factor (ANF),
which was able to promote rapid and massive diuresis and natriuresis
when injected in rats.6–8 Several studies demonstrated that the admin­
istration of ANF produced significant haemodynamic effects, such as
vasodilatation, blood pressure (BP) reduction, haematocrit increase
and increased glomerular filtration rate, in both animals and hu­
mans.9–12 ANF antagonized angiotensin II-induced contraction in iso­
lated aorta, explaining the greater sensitivity to the BP-lowering
effect of ANF in renin-dependent hypertension with elevated levels
of angiotensin-II and aldosterone.9,13 In humans, ANF lowered aortic
pressure in essential hypertension.14 In heart failure (HF) patients,
ANF infusion increased absolute and fractional sodium excretion and
urine flow rate and reduced plasma renin and aldosterone levels.15
As a result of these pioneering studies, the main endocrine cardiovas­
cular functions of these cardiac hormones were progressively charac­
terized and identified in increased natriuresis, diuresis and vasorelaxation
homeostasis.10
After the discovery of ANF, subsequently re-named atrial natriuretic
peptide (ANP), other biologically active peptides of the natriuretic peptide
(NP) family, the brain NP (BNP) and the C-type NP (CNP) were identified.
ANP and BNP are synthetized mainly in the heart and to a lesser extent in
other organs.16 CNP is mainly produced by endothelial cells (ECs) and
lacks the carboxyl-terminal of ANP and BNP.17–19 Although BNP was ori­
ginally isolated from porcine brain, is mostly expressed in the cardiac atria.
ANP and BNP produce similar endocrine responses promoting intense
natriuretic/diuretic effects, while CNP is mostly involved in regulating
blood vessel tone through a paracrine function.19
The heart as an endocrine organ
Beside the production and secretion of NPs, multiple substances acting as
endocrine and paracrine hormones are released by cardiomyocytes and
other cell types within the heart.20–22 Growth differentiation factor 15
(GDF-15), a divergent member of the transforming growth factor
(TGF)-β family, once released into the circulation exerts, among other
functions, the control of body growth through the glial derived neuro­
trophic factor receptor α–like (GFRAL). Myostatin, a member of the
TGF-β superfamily, acts as an endocrine hormone targeting skeletal muscle
to modulate muscle mass through activin receptors. Both hormones, de­
riving from pre-propeptides, are increased in coronary heart disease
(CHD) and HF.21 Other factors released from the heart, including pro­
teins, lipids, and small molecules such as microRNAs (miRNAs) and exo­
somes, mainly exert autocrine/paracrine functions.21 In fact, they
contribute to regulate myocyte growth, inhibition of fibroblast prolifer­
ation and extracellular matrix deposition, coronary endothelium, and vas­
cular smooth muscle cell (VSMC) proliferation and contractility,
myocardial perfusion, and vascular remodelling. In the specific, GDF-15
and follistatin (both members of the TGF-β family) reduce the ischae­
mia/reperfusion injury and the pressure overload-induced hypertrophy.
The fibroblast growth factors (FGFs) decrease cardiac fatty acid oxidation
and inhibit excessive autophagy. Endothelin-1 (ET-1) and activin-A pro­
mote cardiomyocyte survival. The soluble suppression of tumourigenesis-2
and FGFs prevents cardiac fibrosis.21,23–28
Natriuretic peptides in clinical practice
The regulation of gene expression,
secretion, and clearance of
natriuretic peptides
The hallmarks of ANP and BNP production by cardiomyocytes include
regulated secretion from the secretory granules and proteolytic pro­
cessing leading from precursors to mature and biologically active pep­
tides or inactive fragments17 (Figure 1).
Cardiomyocytes store prohormones, namely proANP and proBNP,
in secretory granules. These pro-peptide hormones are enzymatically
cleaved by proprotein convertases (corin and furin) and processed to
form the N-terminal (NT) peptides NT-proANP and NT-proBNP
and the biological active free carboxyl group (COOH)-terminal pep­
tides ANP and BNP29,30 (Figure 1). Further processing of
NT-proANP generates the release of three biologically active frag­
ments, namely proANP1–28 (long-acting NP), proANP31–67, and
proANP78–98.31,32 Differently from ANP, human proBNP shows post-
translational glycosylation within the amino-terminal region.33
The binding of COOH-terminal peptides with type C NP receptor
(NPRC) is followed by internalization and lysosome degradation. The neu­
tral endopeptidase neprilysin (NEP) and the kidneys contribute to the NPs
clearance. Due to its longer half-life compared to ANP (12–20 vs. 0.5–
4 min), BNP exhibits enhanced natriuretic and diuretic actions.
In normal human plasma, the major circulating form of ANP is the
COOH-terminal peptide (αANP). The unprocessed proBNP circulates
in plasma along with BNP and NT-proBNP. Several studies documen­
ted that black individuals carry lower circulating levels of both
NT-proBNP and BNP and of midregional ANP (MRproANP), demon­
strating a state of NP deficiency in the Black race as a likely consequence
of increased clearance rather than reduced synthesis.34,35
Many mechanisms contribute to the synthesis and secretion of ANP
and BNP. Acute (hours), subacute (days), and chronic (weeks) haemo­
dynamic and neurohormonal stimuli produce a different response.36
Acute mechanical stretches stimulate a phasic, short-term burst of
NPs secretion from the existing atrial pool (regulated secretion), with­
out clear effects on their synthesis.36 In subacute haemodynamic load
conditions, circulating NPs derive from both stored and newly synthe­
sized hormones (regulated and constitutive secretion). In conditions of
chronic haemodynamic overload, such as hypertension and HF, synthe­
sis of ANP and BNP occurs both in atria and ventricles.37
Regarding the cellular sites of NPs production, earlier data showed
that the ventricles do not normally contain large amounts of ANP or
BNP, except some areas restricted to the proximal Purkinje system.6
Subsequent studies showed that NPs synthesis and secretion may be
differently regulated in atrial compared to ventricular cardiomyocytes
and in neonatal vs. adult life. Indeed, electron microscopy studies de­
monstrated that secretory granules are not displayed in ventricular car­
diomyocytes from normal hearts, whereas they may be observed in
samples of ventricular myocardium collected during surgery or endo­
cardial biopsies in patients with cardiac disease,38 thus suggesting a pre-
programmed expression of foetal genes in ventricular cardiomyocytes
under pathological conditions. Cardiac catheterization data in humans
with left ventricular (LV) hypertrophy showed that the abnormal
NPs circulating levels were significantly derived from atrial sources.39
Morphological data from immunocytochemistry and in-situ hybridiza­
tion studies in animal models supported the view that NPs production
is normally restricted to the atria and, more specifically, to the auricular
appendages. In an experimental dog model of early LV dysfunction,
BNP mRNA and tissue BNP content were markedly increased in the
645
left atrium along with an increase in circulating BNP, but they remained
below or at the limit of detection in the LV. In overt HF, BNP mRNA
was further increased in the left atrium and in the LV, together with
a BNP increase in LV and blood, probably due to an additional recruit­
ment of ventricular BNP expression.40 These data suggest that the atrial
secretion of BNP might not be sufficient and adequate to counteract
pressure and volume increases as well as hyperactivation of sodium-
retaining and vasopressor neurohormones during HF progression.
In patients who had undergone orthotopic heart transplantation
(with the native atria being left), plasma levels of NPs were not normal­
ized by the replacement of the diseased ventricles even after the nor­
malization of intracardiac pressures. This suggests that the atria are
the main source of NPs also in advanced HF41,42 and that the ventricular
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production is limited to advanced pathological conditions and strongly
depends on ventricular alterations such as those observed in hyper­
trophy, fibrosis, inflammation, and hypoxia. In the latter context, the
hypoxia-inducible factor-1a, produced under low oxygen conditions,
activates transcription of both NPPA and NPPB, the genes encoding
ANP and BNP, respectively.43
In addition to mechanical stimuli, several neurohormonal triggers may
contribute to the secretion of NPs such as angiotensin II, adrenergic ago­
nists, ET-1, arginine vasopressin, glucocorticoids, thyroid hormones, sex
steroids, growth factors, and cytokines (tumour necrosis factor, interleu­
kins −1 and 6), further supporting the role of the heart as a component
of the endocrine system.44,45 More recently, an involvement of glucagon-
like peptide-1, one of the incretin hormones secreted by the epithelium
of the small intestine, has been implicated in the regulation of cardiac
ANP secretion.46
The abovementioned factors can regulate the expression of both
NPPA and NPPB through the same transcriptional factors, including
the rat sarcoma (RAS)/rapid accelerated fibrosarcoma (c-Raf-1) and
the phosphoinositide signalling pathways which stimulate the
p38-mitogen-activated protein kinase.47
An emerging issue is represented by the epigenetic regulation of NPs
synthesis. Different studies have detected epigenetic changes, consisting
in histone acetylation and methylation, in adult cardiomyocytes exposed
to pathological conditions.48 Within the heart, both pressure and vol­
ume overloads have been associated with an increased acetylation of
H3 and H4 histones and with demethylation of H3K9 at both NPPA
and NPPB.49,50 The histone demethylase JMJD2A modulates NPPB in
angiotensin II and ET-1 induced cardiac hypertrophy in human-induced
pluripotent stem cells.51 A reduced expression of three histone
methylation-related molecules (H3K4me3, H3K9me2, and H3K9me3)
was detected in non-ischaemic dilated cardiomyopathy.52
DNA methylation may affect gene function and repress transcription by
altering promoter DNA accessibility and blocking the binding of transcrip­
tion activating proteins.53–55 Aberrant DNA methylation of NPPA may par­
ticipate in the mechanisms of cardiovascular disease (CVD), and it may
serve for the identification of individuals at high risk for CVD for primary
prevention and as a potential molecular target for therapeutic purposes.
Interesting data have been reported regarding the regulation of NPs by
microRNAs.56 Three miRNAs are known to modulate NPPA expression:
miR-425, miR-155, and miR-105.57–59 They act in the presence of the wild
type gene sequence but not when a single base-pair mutation falls within
the miRNA binding site. Consequently, higher ANP levels are detected
in individuals carrying the minor allele at one of these sites such as the min­
or G allele at rs5068, which does not bind miR-425.48 The higher ANP
plasma level detected in carriers of the minor G allele at rs5068 was related
to lower BP level, lower risk of hypertension, lower body mass index and
waist circumference, lower prevalence of obesity, and metabolic
646
Figure 1 Secretion of atrial natriuretic peptide and brain natriuretic peptide in cardiomyocytes takes place through both regulated pathways from
mature secretory granules stored in the cytoplasm and the constitutive pathway involving a de novo peptide synthesis and the release of immature
granules into the cytoplasm. The N-terminal pro-natriuretic peptides processing through corin and furin allow the production of the amino terminal
peptides and the carboxyterminal peptides forms that circulate in the blood.
syndrome.60–62 An increased expression of cardiac miR-425 and of its cir­
culating level has been reported in Blacks as a likely contributor to their basal
NP-deficient state and to the abnormal response to a high-carbohydrate
challenge.35 In fact, the decrease of plasma MRproANP, detected in re­
sponse to a metabolic perturbation such as the high-carbohydrate chal­
lenge, was significantly reduced in Black compared to White individuals.35
NPPA AS1 belongs to the class of natural antisense transcripts and,
as a long noncoding RNA, overlaps the coding protein gene but is
transcribed from the antisense strand. In fact, it inhibits the transcrip­
tion of the corresponding sense mRNA behaving as a natural feedback
mechanism. Consistently, NPPA-AS1 inhibition produced increased
plasma ANP level, increased renal cyclic guanosine-monophosphate
(cGMP) level, and reduced BP level in mice.63 This approach, that
has relevance during mammalian foetal heart development, in condi­
tions of biomechanical stress and in HF, may reveal useful for
therapeutic purposes. An additional mechanism of NPPA modulation
depends on a corin-miRNA-1–3p axis responsible of a potent inhib­
ition of corin activity and therefore of NPPA transcription, as shown
by Celik et al.64
Autocrine/paracrine functions of
natriuretic peptides within the
heart and vasculature
Beside the natriuretic, diuretic and vasorelaxant effects, NPs exert
autocrine/paracrine functions. In the heart, they contribute to the regu­
lation of myocyte growth, inhibition of fibroblast proliferation and
extracellular matrix deposition. They exert cytoprotective anti-
M. Volpe et al.
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ischaemic function and regulate myocardial perfusion and remodel­
ling.65 A newly discovered autocrine property of ANP is the regulation
of cardiac autophagy, a process devoted to the removal of damaged
cells and organelles, to protect the heart from ischaemic insult.66
These functions, similarly to the endocrine functions, are mediated
through the type A NP receptor (NPRA)67,68 (Figure 2).
The genetic ablation of either NPPA or Npr1 (the gene encoding
NPRA) produced cardiac hypertrophy in mice.69,70 Consistently, genet­
ic variants of NPPA responsible of reduced ANP expression were asso­
ciated to cardiac hypertrophy in humans.71 A marked cardiac fibrosis
was detected in mice lacking NPPB.72 Conversely, high concentrations
of NPs modulate cardiomyocyte numbers during development oppos­
ing cardiomyocyte proliferation.73
ANP also exerts anti-inflammatory, proliferative, pro-angiogenic, and
anti-apoptotic effects within the endothelium.74 Lack of ANP as well as
a structurally altered ANP variant derived from a human gene mutation
associate with impaired EC viability and proliferation.75 BNP, produced
by satellite cells within ischaemic skeletal muscle or by cardiomyocytes
in response to pressure load, promotes endothelial protection via
NPRA.76 More recently, the modulation of pericytes and microcircula­
tory tone within the kidneys has been associated to the acute and
chronic modulation of arterial BP by ANP.77
CNP plays a physiological autocrine role in cardiovascular homeosta­
sis by acting at the vascular level through the type B NP receptor
(NPRB).78 It is also known as a key hormone for bone growth, as shown
by the systemic CNP KO mice.79 CNP is a major member of the
non-NO, non-prostanoid component of endothelium-dependent re­
laxation in the resistance vasculature. Endothelium-derived CNP con­
tributes to the chronic regulation of vascular tone and systemic BP
Natriuretic peptides in clinical practice 647

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Figure 2 The signalling pathways of the three natriuretic peptide receptors are represented. Type A and B natriuretic peptide receptors stimulate the
formation of cyclic guanylate monophosphate through the activation of particulate guanylate cyclase. The stimulation of guanylate cyclase activity takes
place also through the NO-soluble guanylate cyclase pathway. The two pathways do not necessarily share common molecular mechanisms, though the
final effects coincide. Cyclic guanylate monophosphate produces PKG, CNG, and PDEs. While PKG allows the biological functions of natriuretic pep­
tides in target tissues, phosphodiesterases metabolize cyclic guanylate monophosphate and reduce its effects. Activation of type C natriuretic peptide
receptor by C-type natriuretic peptide leads to the inhibition of adenylate cyclase, stimulation of phospholipase C, extracellular signal regulated kinase,
and phosphoinositide 3-kinase/protein kinase B. These pathways mediate the cardiac and vascular effects of C-type natriuretic peptide described by
references79–83. The final cardiovascular and renal effects of natriuretic peptides mediated by the three receptors are reported in the figure.
Abbreviation: CNG, gated-ion channel; PKG, protein kinase G; NO, nitric oxide.

by maintaining endothelial function and integrity independently of
NPRB.80 Moyes et al.81 underscored the relevance of NPRC signalling
as the main mechanism underpinning CNP-dependent vascular pro­
tective functions (Figure 2). Consistently, the administration of NPRC
agonists promoted vasorelaxation in isolated resistance arteries and a
BP reduction that was not observed in mice lacking NPRC. Within
the heart, CNP derived from ECs, cardiomyocytes, and fibroblasts co-
ordinates and preserves cardiac structure, function, and coronary va­
soreactivity via activation of NPRC.82
Interactions between cardiac and
other endocrine systems
An interaction between the NPs and adipose tissue has been consistent­
ly described. Indeed, the antihypertrophic effect of some adipokines,
such as leptin, resistin, and visfatin, is linked to a stimulatory action on
ANP and BNP secretion in the heart of ob/ob mice.83 In turn, NPs
play a role in the regulation of fat tissue function and growth by activating
lipolysis, enhancing lipid oxidation, postprandial energy expenditure, and
mitochondrial respiration.84 NPs also exert metabolic actions and acti­
vate the co-transcriptional activator peroxisome proliferator-activated-
receptor-G-coactivator (PGC)-1α and the proliferator-activated
receptor-d, promoting muscle mitochondrial biogenesis and fat
oxidation.85 Recently, CNP has emerged as a regulator of energy metab­
olism through the control of adipogenesis, thermogenesis, and glucose
clearance through NPRB and NPRC, triggering increases in cGMP and
decreases in cAMP, respectively.86
A still unexplained issue is represented by the lower NPs circulat­
ing levels found in obese compared with lean healthy subjects. An in­
creased expression of the NPRC in fat tissue can contribute to
explain this finding. The increased production of some adipokines re­
leased by visceral fat tissue may also play a role. Finally, reduced car­
diac secretion of NPs or impaired synthesis may contribute to lower
plasma NP levels in obesity.87 Moreover, ANP potentiates the effect
of glucagon-like peptide 1 (GLP-1) on glucose-induced insulin
secretion.88
Regarding the interaction between the NP system and steroid hor­
mones, experimental studies demonstrated that female sex steroids in­
crease NPPA expression in a dose-dependent manner and that both
oestradiol and progesterone are necessary to maintain suitable levels
of NPPA expression in rat cardiomyocytes. On the other hand, the
ANP concentration and atrial stores were increased in castrated
male rats. The testosterone replacement was associated with a de­
crease of plasma ANP concentration, but not of atrial stores. The ex­
perimental data suggest that both female and male sex steroid
hormones influence NPs secretion, although with opposing effects.89
Moreover, hormone replacement therapy has shown a stimulatory ac­
tion on the secretion of NPs in postmenopausal women.90 Regarding
adrenal corticosteroids, an inverse relationship with NPs has emerged
from different studies. While corticosteroids have direct and indirect
stimulating actions on cardiac endocrine function, NPs inhibit the secre­
tion of corticosteroids both directly, through the specific receptors on
zona fasciculata and glomerulosa cells, and indirectly by inhibiting the
RAS.91 ANP is more potent than BNP in inhibiting the aldosterone re­
sponse to angiotensin-II.92
648
Figure 3 Schematic representation of the interactions between
natriuretic peptides and phosphodiesterases. Cyclic guanosine-
monophosphate stimulates the production of phosphodiesterase 2
and phosphodiesterase 5, whereas it antagonizes phosphodiesterase 3.
Also, phosphodiesterase 1 and phosphodiesterase 9 metabolize cyclic
guanosine-monophosphate. Cyclic adenylate monophosphate is mainly
metabolized by phosphodiesterases 2, 3, 4, 8.
Impaired endocrine response of the
heart
The ‘endocrine paradox’ in HF is related to the observation that fluid
retention and vasoconstriction occur despite high or very high circulat­
ing NPs levels. Early evidence in the ’90s showed that plasma ANP levels
were not properly increased by volume expansion with saline solution
in patients with dilated cardiomyopathy and mild cardiac systolic dys­
function, before the onset of signs or symptoms of overt HF. The in­
appropriate increase of ANP levels might contribute to the abnormal
vasoconstriction and water/sodium retention in HF patients exposed
to acute or chronic volume overload.91 Moreover, failure to suppress
plasma renin activity in hypertensive patients in response to acute saline
load, along with an abnormal ANP response, was explained by an im­
paired relationship between increases of blood volume and those of at­
rial pressure or wall stress during saline infusion.93 Resistance to the
biological effects of NPs can be attributed to different mechanisms, act­
ing at pre-receptor, receptor, and post-receptor levels. Regarding the
pre-receptor level, an impaired post-translational processing of
proNPs has been hypothesized.48 Indeed, increased levels of circulating
non-biologically active proBNP-derived fragments have been identified
by chromatographic procedures in human plasma, consisting in the in­
tact and glycosylated forms of the precursor proBNP and
NT-proBNP.94 Furthermore, plasma corin levels are significantly lower
in HF patients than in controls with a relationship between reduced
plasma enzyme levels and disease severity. Corin and furin cleavage
of proBNP into active BNP could be suppressed by the glycosylation
of proBNP near to the cleavage site of the enzymes, which makes
the molecule resistant to proteolysis.30 In HF patients carrying a higher
proportion of proBNP a higher glycosylation rate at threonines 48 and
71 with a consequent reduction of its processing was described. The
GalNac-transferase (GALNT) 1 and 2 mediate the glycosylation-
regulated increase of proBNP secretion in these subjects. Of interest,
M. Volpe et al.
a miR30-GALNT1/2 axis is a mechanism responsible of the increased
secretion of inactive proBNP in HF, likely contributing to the NPs re­
sistance and to the disease progression.95
Regarding the mechanisms of resistance at the receptor level, an in­
creased expression of the NPRC in some peripheral tissues may play a
role, by reducing the circulating levels of active NPs. Other studies showed
that gene variants of NPs receptors may contribute to the development of
CVDs, such as cardiomyopathies and stroke.61,62 Downstream to the NP
receptors, cyclic nucleotide-dependent intracellular molecular pathways
are regulated by phosphodiesterases (PDEs), which metabolize the
cGMP (Figure 3). PDEs are involved in complex cellular responses and their
dysregulation may contribute to an increased resistance to NPs in CVDs.96
Based on both experimental and human studies, PDEs 1–5, 8, and 9 are
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dysregulated in HF.36 The post-receptor regulation of NPs activity oper­
ates through the binding with the G-coupled receptors NPRA and
NPRB and the subsequent stimulation of a membrane-bound particulate
guanylate cyclase (pGC), thus improving endothelial function, reducing pul­
monary pressures and increasing cardiac output.97,98 In such a context,
strategies based on activation/stimulation of the NO-soluble GC pathway
might have synergistic effects with NPs in HF.
Natriuretic peptides as markers
of cardiovascular diseases
NPs have been validated as useful diagnostic and prognostic biomarkers
in CVDs. In addition to being well-established diagnostic and prognostic
markers of HF, plasma levels of NPs have been proposed as biomarkers
also in atrial fibrillation, CHD, and valvular heart disease.
In the non-acute HF setting, the upper limits of normal levels are
35 pg/mL for BNP, 125 pg/mL for NT-proBNP, and 120 pg/mL for
mid regional-proANP (MR-proANP).99 BNP and NT-proBNP levels
are currently used in clinical practice to confirm the diagnosis of HF
and are associated with disease severity. Based on knowledge that high­
er NT-proBNP levels, besides reflecting more severe heart disease, de­
pend on age, female sex, and renal function, the range of normal levels in
older people and other clinical settings needs to be further defined.
Table 1 summarizes available evidence regarding the diagnostic and
prognostic role of NPs in CVDs.99–118
Role of natriuretic peptide–based
strategies to prevent heart failure
The use of BNP has been successfully introduced in programmes of HF
prevention.119–121 The St. Vincent’s Screening to Prevent HF
(STOP-HF) included asymptomatic individuals with one or more risk
factors of CVD. The trial compared a BNP-based screening based on
a collaboration between primary care physicians and cardiologists.
The control group received the primary care physician and specialist
care when required. The intervention group showed a reduction in
HF development.122 Consistently, a genetic sub-study of the
STOP-HF trial revealed that the minor C allele of a BNP genetic variant,
rs198389, associated with higher circulating BNP levels, was associated
with lower risk of hypertension, new onset LV dysfunction or major ad­
verse cardiovascular events.123 The PONTIAC study used the
NP-based approach as part of a strategy to identify subjects at the high­
est risk of cardiovascular events, targeting treatment to these groups to
prevent HF and other CVDs. The study included 300 diabetic patients
free from CVD but with increased NT-proBNP level, who were
Natriuretic peptides in clinical practice 649

Table 1 Diagnostic and prognostic role of NPs in CVDs

Natriuretic peptide Clinical conditions

......................................................................................................................................................................................
NT-proBNP Diagnostic role in acute, subacute, and chronic HF99,100
ACS,101 pulmonary embolism,102 pulmonary hypertension103,104
Prognostic role for increased risk of stroke, systemic embolism, and cardiac-related death in patients with AF, improving the
CHA2DS2-VASc score105
Markers of cognitive decline and dementia consequent to brain microcirculatory damage and dysfunction in hypertensive
patients106
NT-proANP and Markers of progression of coronary atherosclerosis from moderate to severe101
NT-proBNP

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NT-proANP and BNP Predictor of future CV events, including death and recurrent MI, in stable CAD patients101,107
Predictor of future CV events following coronary revascularization (PCI/stent)108,109
BNP Increased levels are associated with severity of aortic stenosis, LV chamber size, wall thickness and stress, LVEF, left atrial size,
and right ventricular pressure110
J-shaped relationship with all-cause and cardiovascular mortality rates in HFpEF patients undergoing TAVR111
Increased levels are directly related with mean pulmonary arterial pressure in patients with pulmonary hypertension112
NT-proBNP and BNP Increased levels assess the progression of mitral valve disease, contribute to more accurate risk stratification by identifying
patients who are more likely to experience death from CV causes, HF, and cardiac hospitalizations113
NT-proANP Prognostic role towards digital ulcers development and mortality in systemic sclerosis patients114,115
MR-proANP Diagnostic role in acute and sub-acute HF116 Prognostic role in HCM117
MR-proANP combined with Improved prognostic role in HF118
BNP

ACS, acute coronary syndrome; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CAD, coronary artery disease; CV, cardiovascular; HCM, hypertrophic cardiomyopathy; HF, heart
failure; HFpEF, heart failure with preserved ejection fraction; LV, left ventricle; LVEF, left ventricular ejection fraction; MR-proANP, mid-regional pro-atrial natriuretic peptide; NT-proANP,
N-terminal pro-atrial natriuretic peptide; NT-proBNP, N-terminal pro-brain natriuretic peptide; PCI, percutaneous coronary intervention; TAVR, transcatheter aortic valve replacement.

randomized to either standard treatment or an intensified strategy in­
volving a cardiac outpatient clinic. As a result, the intensified treatment
led to a significant reduction of CVD development, HF, and hospitaliza­
tions.124 Interestingly, the incorporation of NPs levels to clinical infor­
mation led to superior risk prediction of HF, compared to a model only
incorporating risk factors, among individuals with dysglycaemia.124
Both the STOP-HF and PONTIAC trials are included in the 2014
Canadian Cardiovascular Society HF Management Guidelines to sup­
port a recommendation for the use of NPs in at-risk individuals.125
These guidelines recommend that NPs levels should be used to imple­
ment strategies to prevent HF in individuals with risk factors.
Based on the high diagnostic and prognostic value of NPs levels in the
preclinical stage of HF and other CVDs, the use of NPs measurement in
the clinical practice should be recommended.
Beside their role as biomarkers of HF severity, the results of different
studies have suggested that serial measurements of NPs may be helpful
to guide titration of long-term medical therapy in HF. Indeed, it has
been shown that patients randomized to receive biomarker-guided
therapy achieved a greater decrease in NPs levels over time compared
with those kept in the usual care strategy, these changes being asso­
ciated with improvements in clinical outcomes.126
Current therapeutic implications of
cardiac endocrine function
For many years, the potential advantages of NPs properties in HF have
encouraged the development of drugs which could mimic or enhance
NPs activity.127 After a series of unsuccessful attempts by using NPs ana­
logues with longer half-life of the naturally occurring NPs, NEP inhibitors
alone, or in combination with ACE-inhibitors, the pharmacological regu­
lation of the endocrine function of the heart has resulted in the thera­
peutic combination of the angiotensin receptor inhibitor valsartan
with the NEP inhibitor (ARNi) sacubitril. NEP is also involved in the deg­
radation of other biological active peptides including bradykinin and
angiotensin II.128 Therefore, the concomitant inhibition of type 1 angio­
tensin II receptor (AT1R) and of NEP, achieved by combining sacubitril
and valsartan, produces a synergistic effect by increasing NPs levels and
reducing the angiotensin II-related signal transduction pathways.129
Experimental studies assessed the impact of ARNi on the circulating
NPs levels.130 A human study by Murphy et al.131 considered 23 patients
with mild to moderate HF with reduced ejection fraction (HFrEF) and
measured BNP using 5 different assays, NT-proBNP using 3 assays,
and ANP, MR-proANP, proBNP,1–107,132 and CNP using a single assay
before and 22, 46, and 84 days after initiating sacubitril/valsartan therapy.
As a result, sacubitril/valsartan led to small and inconsistent changes in
BNP (that varied across the methods), to a decrease of variable extent
of MR-proANP, NT-proBNP, and proBNP,1–107,132 whereas CNP levels
did not show any consistent change. The most striking result, consistent
with the experimental evidence, was a highly significant increase of
αANP, suggesting a role for this peptide. N-terminal peptides are char­
acterized by major stability and, since they are not cleared by NEP, are
the only measurable fragments during ARNi treatment. Since the publi­
cation of the proof-of-concept study PARADIGM-HF (Angiotensin
650 M. Volpe et al.

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Figure 4 The impact of neprilysin on atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide metabolism ultimately in­
creases the level of the carboxyterminal peptides in the circulation with consequent beneficial effects for the cardiovascular system. The decrease
of the circulating amino terminal peptides observed upon ARNi administration mirrors the improvement of cardiac function. The increased brain natri­
uretic peptide level, such as that occurring in chronic heart failure, has been suggested to behave as an endogenous inhibitor of neprilysin.

Receptor-Neprilysin Inhibitor with ACEI to Determine Impact on Global
Mortality and Morbidity in HF),133 the benefits of sacubitril/valsartan in
chronic and acute HFrEF setting have been consistently demon­
strated.134–137 More recently, sacubitril/valsartan has been associated
with a significant reduction in CV mortality and HF hospitalizations across
a wide range of the ejection fraction (EF) spectrum.138,139
Based on this evidence, European Guidelines recommend sacubitril/val­
sartan as first-line treatment in HFrEF and suggest considering its use in HF
with mildly reduced EF (40%–49%).99 Moreover, US Food and Drug
Administration approved an expanded indication for sacubitril/valsartan
in HF with preserved EF (HFpEF) patients or independently of LVEF.140
In contrast with the above-mentioned studies, patients with chronic
advanced HFrEF included in the LCZ696 (sacubitril/valsartan) in the
Hospitalized Advanced Heart Failure (LIFE) trial did not significantly re­
duce the NT-proBNP level when treated with sacubitril/valsartan com­
pared to valsartan.141 Among other plausible explanations, a
BNP-mediated NEP inhibition might have contributed to the unexpect­
ed results. Indeed, based on a previous study, BNP levels >916 pg/mL
behave as an endogenous NEPi.142 Thus, NEP might be already inhibited
by high BNP level in patients with advanced HF, without any additional
benefits upon sacubitril/valsartan treatment143 (Figure 4). If this hypoth­
esis is corroborated by more direct evidence, it may support alternative
strategies to enhance the NP actions, such as the stimulation of NP
receptors.
In the PARADISE-MI (Prospective ARNI vs. ACE Inhibitor Trial to
Determine Superiority in Reducing Heart Failure Events after
Myocardial Infarction) study conducted in patients with acute myocar­
dial infarction no significant differences in the composite outcome of
cardiovascular death, HF hospitalizations or outpatient development
of HF were found between sacubitril/valsartan and ramipril.144
However, a superiority of sacubitril/valsartan has been reported in a
recent post-hoc analysis of the study including only investigator-
identified events.145
Future perspectives for therapeutic
implications of natriuretic peptides
in cardiovascular diseases
Experimental studies in mice showed that the NPPA knockout led to salt-
sensitive hypertension and lack of Npr1 associated with salt-sensitive
hypertension. Intravenous ANP administration in a model of
EC-specific, but not VSMC-specific, deletion of Npr1 resulted in dimin­
ished BP reduction, highlighting the role of endothelial NPRA for BP and
vascular tone regulation by ANP.146 In humans, molecular genetic stud­
ies have revealed that reduced NPs expression contributes to an in­
creased occurrence of hypertension, these results being confirmed by
genome-wide association studies23 and by the evidence that primary
hypertension is a condition of ANP deficiency.147 Based on this patho­
physiological and genetic background, several NP-based therapeutic ap­
proaches, including ANP-recombinant peptides (carperitide and
ularitide), endothelin converting enzyme/neprilysin inhibitors, and
ARNi have been developed in hypertension.148 However, no significant
benefits were obtained, and an excess of adverse events was reported.
More recently, a novel ANP-based compound (M-atrial natriuretic pep­
tide [MANP]), a potent NPRA stimulator with a greater resistance to
enzymatic degradation by both NEP and insulin degrading enzyme and
reduced removal by NPRC, has shown long lasting and dose-dependent
BP lowering effect and no relevant short-term adverse effects.149,150
MANP, a 40 amino acid peptide compared to 28 amino acids ANP, car­
ries a natural peptide mutation firstly discovered in a family affected by
AF.151 The clinical development of this innovative NP-based approach
Natriuretic peptides in clinical practice 651

Table 2 summarizes the main therapeutic strategies based on inter­

Table 2 Therapeutic strategies based on NPs
ventions on the NP system.48–52,57,63,98,133–139,149–151,155–169
Level of Therapeutic strategies
intervention
.................................................................................... Conclusions
NPPA and NPPB NPPA-AS1 (long noncoding RNA and natural
expression antisense transcript for NPPA)63 Studies performed in the last 40 years have consistently supported that
the heart has an endocrine function exerted through the action of dif­
microRNAs inhibiting the NPPA expression:
ferent hormones. The NP system appears to play a prominent role in
miR-425, miR-155, miR-10557–59
physiological and pathological cardiovascular conditions and to interact
Histone acetylation and DNA methylation48–52 with extracardiac hormonal systems.
Reduction of NEPi (Candoxatril)155 The three main components of the NP system act through specific
NPs receptors and intracellular signalling pathways. ANP and BNP are most­
ACE/NEPi (Omapatrilat)156

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degradation
ARB/NEPi (Sacubitril/valsartan)133–139
ECE/NEPi (Daglutril)157
NPR activation Nesiritide (synthetic human BNP)158
Carperitide, Ularitide (recombinant human ANP)159
Cenderitide (CD-NP)160
Vosoritide (analogue of human CNP)161
Designer peptides: MANP149–151 ASBNP.1 (derived
from an alternative spliced transcript form of
BNP)162 Conjugated ANP
(ANP-Fc, ANP-HSA, CNP/ANP)163,164
Triazine derivatives (GC-A non-peptide
activators)165
Activating antibodies163
GC-A positive allosteric modulators
(MCUF-651)166
Post-receptor PDE inhibitors167
enhancers
sGC stimulators (vericiguat)98,168
sGC activators169
ACE, angiotensin converting enzyme; ANP, atrial natriuretic peptide; ANP-Fc, ANP
fused to the Fc domain of IgG; ANP-HSA, recombinant human ANP and human
serum albumin; ARB, angiotensin receptor blocker; BNP, brain natriuretic peptide;
ASBNP.1, alternatively spliced; CNP, C-type natriuretic peptide; ECE;
endothelin-converting enzyme; GC-A, guanylyl cyclase A receptor; MANP, novel
ANP-based compound; miR; microRNA; NEPi; neprilysin inhibitor; NPs, natriuretic
peptides; NPPA, gene encoding ANP; NPPB, gene encoding BNP; NPR, natriuretic
peptide receptor; PDE, phosphodiesterase; sGC, soluble guanylate cyclase.
may find a role in the management of hypertension and may contribute
to prevent the development of organ damage, HFrEF and HFpEF.152
Another fragment derived from the NT-proANP, the proANP 31–67
peptide, has shown cardiorenal protective actions, independently
from the NPR/cGMP pathway, in a preclinical model of maladaptive car­
diac hypertrophy and renal damage induced by hypertension.153 It ap­
pears a promising therapeutic tool to counteract hypertensive organ
damage, renal diseases, and HF.32
Thanks to the growing knowledge on synthesis, secretion, and regu­
lation of NPs, new strategies can be developed. The genetic/epigenetic
modulation of NPs represents an attractive approach.154 Therefore,
potential RNA-based targets to achieve an increased level of circulating
NPs include miR-425 and miR-155.57 Furthermore, modulation of
NPPA methylation may serve as a useful tool to change circulating
ANP levels. Currently, work is ongoing to elucidate the therapeutic
benefit of NPPA-AS1 knock-down in models of HFpEF and HFrEF.63
ly involved in the control of cardiovascular homeostasis through their
natriuretic, diuretic, and vasorelaxant effects. CNP is mostly involved
in regulating vascular tone.
Due to their biological properties, components of the NP systems
have been largely validated as useful diagnostic and prognostic biomar­
kers in different CVDs. NP-based therapeutic approaches might re­
present promising future strategies contributing to enhance the
beneficial effects of an efficacious neurohormonal inhibition and to
counteract the development and progression of HF and other CVDs.
Funding
All authors declare no funding for this contribution.
Conflict of interest: M.V. reports personal fees for speaker bureau and/
or consulting in Advisory Board from Amarin, Amgen, Astra Zeneca, Kalos
Medical, Menarini Int, Novartis Pharma, Novo Nordisk, outside the submit­
ted work. S.R. and G.G. have nothing to disclose.
Data availability
There are no new data associated with this article.
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Erratum
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Erratum to: Transfemoral aortic valve implantation: procedural hospital volume and mortality in Germany
This is an erratum to: Kurt Bestehorn, Maike Bestehorn, Ralf Zahn, Christian Perings, Christoph Stellbrink, Volker Schächinger, Transfemoral
aortic valve implantation: procedural hospital volume and mortality in Germany, European Heart Journal, 2022, ehac698, https://doi.org/
10.1093/eurheartj/ehac698
Upon original publication, Figure 1 was inadvertently omitted from the PDF version of this manuscript.
The Publisher apologizes for this error, which has now been corrected.
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Online publish-ahead-of-print 22 December 2022